In the course of synthesis of biologically active arginine containing peptides, the guanidine group of arginine is protected with a nitro group. If it is desirable to treat the nitroarginine containing peptide with a nucleophilic reagent such as hydrazine or ammonia, it is necessary to selectively remove the nitro group because treatment of a nitroarginine peptide with a nucleophile such as ammonia would result in substantial or complete conversion of nitroarginine to ornithine.
In the prior art HF is used to remove the nitro protecting group from nitroarginine peptides. This process results in the complete or partial removal of other protecting groups such as the commonly used t-butyloxycarbonyl (Boc) group. According to the novel process of the present invention, the nitro group is selectively removed without loss of labile protecting groups such as the Boc protecting group.
The isonicotinyloxycarbonyl (i-NOC) group, a widely used protecting group for the .epsilon.-amino group of lysine, is removed by catalytic hydrogenation, electrolysis, and the two electron reducing agent zinc. These methods are also used in the prior art to remove the nitro group from nitroarginyl peptides, thus preventing the selective removal of the nitro group by these methods. According to the novel process of the present invention, the nitro group is selectively removed by treatment with titanium (III) in the presence of other labile protecting groups such as CBZ, Boc, Acm, benzyl, t-butyl and i-NOC.
The abbreviated designations, which are used herein for the amino acid components, certain preferred protecting groups, amino acid activation groups, condensing agents, reagents and solvents employed in the process of this invention are as follows:
______________________________________ Abbreviated Designation Amino Acid ______________________________________ Lys L-lysine Phe L-phenylalanine Trp L-tryptophan Cys L-cysteine Met L-methionine Arg L-arginine Gly glycine Abbreviated Protecting Designation Groups CBZ benzyloxycarbonyl Acm acetamidomethyl i-NOC isonicotinyloxycarbonyl Boc tert-butyloxycarbonyl OMe methyl ester Abbreviated Activating Designation Groups HBT 1-hydroxybenzotriazole Abbreviated Condensing Designation Agents DCCI dicyclohexylcarbodiimide Abbreviated Designation Reagents TFA trifluoroacetic acid TEA triethylamine Abbreviated Designation Solvents EPAW ethyl acetate-pyridine- acetic acid-water BAW butanol-acetic acid- water CMW chloroform-methanol- water DMF dimethylformamide THF tetrahydrofuran MeOH methanol HOAc acetic acid ______________________________________